Targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement

Ng, Adeline Su Lyn; Tan, Yi Jayne; Zhao, Yongxiang; Tandiono, Moses; Chew, Elaine Guo Yan; Dominguez, Jacqueline C.; Macas, Mabel; Ng, Ebonne Yulin; Hameed, Shahul; Ting, Simon; Tan, Eng King; Foo, Jia Nee; Kandiah, Nagaendran

doi:10.1016/j.neurobiolaging.2018.04.003

Cited by 14 publications

(18 citation statements)

References 25 publications

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“…The 6 families affected in this pedigree may benefit from clinical evaluation and testing with plasma GRN, which is indicated for screening possible GRN mutation carriers, especially that all mutation carriers in this family have low plasma GRN levels [39]. This R110X mutation and the 2 novel pathogenic GRN mutations recently documented in 3 Filipinos [40] suggest that there may be more to be found. It could be prudent in the Philippines to consider plasma GRN as an additional test in the evaluation of dementia with atypical presentation and with positive family history, whether early or late onset, and then do further genetic testing afterward.…”

Section: Discussionmentioning

confidence: 94%

“…This R110X mutation and the 2 novel pathogenic GRN mutations recently documented in 3 Filipinos [40] suggest that there may be more to be found. It could be prudent in the Philippines to consider plasma GRN as an additional test in the evaluation of dementia with atypical presentation and with positive family history, whether early or late onset, and then do further genetic testing afterward.…”

Section: Discussionmentioning

confidence: 95%

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Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation

Dominguez

et al. 2020

Dement Geriatr Cogn Disord

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Background: Compared to Western populations, familial frontotemporal lobar degeneration (FTLD) is rare among Asians. Progranulin (GRN) gene mutation, which is a major cause of FTLD, is likewise rare. We present a family with FTLD from the Philippines with an autosomal dominant pattern of inheritance and GRN mutation and briefly review reports of GRN mutations in Asia. Case Presentation: The proband is 66 years old with progressive nonfluent aphasia (PNFA)-corticobasal syndrome . We assessed 3 generations of her pedigree and found 11 affected relatives with heterogenous phenotypes, usually behavioral variant frontotemporal dementia (FTD) and PNFA. Neuroimaging showed atrophy and hypometabolism consistent with FTD syndromes. White matter hyperintensities were seen in affected members even in the absence of vascular risk factors. A GRN mutation R110X was found in 6 members, 3 with symptoms and 3 were asymptomatic. Plasma GRN was low (<112 ng/mL) in all mutation carriers. No mutations were found in microtubule-associated protein tau, APP, PSEN1, and PSEN2 genes, and all were APOE3. Conclusion: This is the first Filipino family with autosomal dominant FTD documented with GRN mutation. Identifying families and cohorts would contribute to therapeutic developments in an area with FTD-GRN.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 95%

Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation

Dominguez

et al. 2020

Dement Geriatr Cogn Disord

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“…TREM2 and TYROBP (encoding DAP12), which together encode a receptor signaling complex expressed in myeloid cells, were first linked to autosomal-recessive Nasu-Hakola disease (NHD; also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) more than 15 years ago [57,58]. Although NHD classically involves early-onset dementia and recurrent bone fractures, a number of patients with FTD-like syndromes lacking a bone phenotype (often with early-onset symptoms) have also been identified who harbor homozygous or compound heterozygous mutations in TREM2 [59][60][61][62][63][64][65]. Moreover, a recent meta-analysis of rare TREM2 variants found that variants p.R47H (rs75932628) and p.T96K (rs2234253) confer an ~2-3-fold increase in risk for FTD in European populations [66]; p.R47H is also a well known AD risk factor [67] and a possible risk factor for PD [68].…”

Section: Trem2 and Tyrobpmentioning

confidence: 99%

Recent Advances in the Genetics of Frontotemporal Dementia

et al. 2019

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Purpose of review: In this review we highlight recent advances in the human genetics of frontotemporal dementia (FTD). In addition to providing a broad survey of genes implicated in FTD in the last several years, we also discuss variation in genes implicated in both hereditary leukodystrophies and risk for FTD (e.g., TREM2, TMEM106B, CSF1R, AARS2, NOTCH3). Recent findings: Over the past five years, genetic variation in approximately 50 genes has been confirmed or suggested to cause or influence risk for FTD and FTD-spectrum disorders. We first give background and discuss recent findings related to C9ORF72, GRN and MAPT, the genes most commonly implicated in FTD. We then provide a broad overview of other FTD-associated genes and go on to discuss new findings in FTD genetics in East Asian populations, including pathogenic variation in CHCHD10, which may represent a frequent cause of disease in Chinese populations. Finally, we consider recent insights gleaned from genome-wide association and genetic pleiotropy studies. Summary: Recent genetic discoveries highlight cellular pathways involving autophagy, the endolysosomal system and neuroinflammation, and reveal an intriguing overlap between genes that confer risk for leukodystrophy and FTD.

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“…Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is an innate immune receptor found on myeloid-lineage immune cells, including dendritic cells, monocytes, and tissue-resident macrophages such as osteoclasts in bone and microglia in the brain (1). Heterozygous variants including R47H and R62H are risk factors for Alzheimer's disease (AD), while homozygous loss-of-function in TREM2 causes Nasu-Hakola disease, a severe, early-onset demyelinating dementia presenting as a frontotemporal dementia (FTD) syndrome with cystic bone lesions (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Neurodegenerative Disease–Associated Variants in TREM2 Destabilize the Apical Ligand-Binding Region of the Immunoglobulin Domain

2019

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Single nucleotide variations in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) have been linked to both late-onset Alzheimer's disease and behavioral variant frontotemporal dementia (FTD), the latter presenting either in isolation or with cystic bone lesions in a condition called Nasu-Hakola disease. Models of the extracellular domain of TREM2 show that Nasu-Hakola disease-associated mutations are grossly inactivating by truncation, frameshift, or unfolding, that Alzheimer's disease (AD)-associated variants localize to a putative ligand-interacting region (PLIR) on the extracellular surface, and that FTD-associated variants are found in the hydrophobic core. However, while these disease-associated residues are predicted to play some role in disrupting ligand binding to the extracellular domain of TREM2, how they ultimately lead to disease remains unknown. Here, we used in silico molecular modeling to investigate all-atom models of TREM2 and characterize the effects on conformation and dynamical motion of AD-associated R47H and R62H as well as FTD-associated T96K, D86V, and T66M variants compared to the benign N68K variant and the common variant. Our model, which is based on a published 2.2 Å resolution crystal structure of the TREM2 extracellular domain, finds that both AD-and FTD-associated variants cause localized instability in three loops adjacent to the PLIR that correspond to the complementarity-determining regions (CDRs) of antibodies. This instability ultimately disrupts tethering between these CDRs and the core of the immunoglobulin domain, exposing a group of otherwise-buried, negatively charged residues. This instability and exposure of negatively charged residues is most severe following introduction of the T66M variant that has been described as causing FTD even in the heterozygous state and is less severe following introduction of variants that are less strongly tied to FTD or of those associated with AD. Thus, Dean et al. Variants Disrupt TREM2 Apical Conformation our results provide further evidence that the proposed loss-of-function caused by neurodegenerative disease-associated variants may be driven by altered conformational stability of the ligand-interacting CDR and, ultimately, loss of affinity or specificity for TREM2 ligands.

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Targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement

Cited by 14 publications

References 25 publications

Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation

Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation

Recent Advances in the Genetics of Frontotemporal Dementia

Neurodegenerative Disease–Associated Variants in TREM2 Destabilize the Apical Ligand-Binding Region of the Immunoglobulin Domain

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